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ERC-AG - ERC Advanced Grant

Cel

"T cells probe the surface of dendritic cells (DCs) in search of cues reflecting the antigenic and the inflammatory status of the body tissues. The INTEGRATE project aims at using innovative genetic and proteomic tools to describe under physiological conditions and at the systemic levels the molecular signals that results from the encounter of T cells and DCs and that are at the basis of adaptive immunity. This project is based on a constellation of pilot experiments that support its feasibility. It will capitalize on 15 novel lines of knockin mice that will allow us to generate via Mass Spectrometry a high-density set of quantitative data describing the TCR signaling network of primary CD4+ and CD8+ T cells and of Foxp3+ regulatory T cells. INTEGRATE will also include innovative genetic approaches to analyze the T-cell intrinsic regulatory mechanisms that terminate T cell activation and the malfunctions of which are at the basis of inflammation and autoimmunity. Since the study of DCs is mandatory if we are ever to make sense of the complexity of T cell activation, a segment of the INTEGRATE project will be devoted to disentangle the function of key DC subsets in vivo. Four aims will be addressed using multidisciplinary approaches:AIM 1: Defining via MS the composition and dynamics of the signaling complexes that assemble around 17 nodes of the TCR signaling cascade of primary CD4+ and CD8+ T cells and in regulatory T cells.AIM 2: Determining how mutations that reduce TCR signaling output paradoxically lead to autoimmune pathologies.AIM 3: Disentangling the function of dendritic cell subsets in vivo using innovative genetic tools.AIM 4: Integrating the T cell- and the DC-side and defining the masterswitch(s) between tolerance and immunity.It is thus expected that the INTEGRATE project will permit to understand at the system levels the flow of information in T cells stimulated under physiological conditions by well-defined subsets of DCs."